The present invention relates to pyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
The immune system is comprised of innate and acquired immunity, both of which work cooperatively to protect the host from microbial infections. It has been shown that innate immunity can recognize conserved pathogen-associated molecular patterns through toll-like receptors (TLRs) expressed on the cell surface of immune cells. Recognition of invading pathogens then triggers cytokine production (including interferon alpha (IFNα)) and upregulation of co-stimulatory molecules on phagocytes, leading to modulation of T cell function. Thus, innate immunity is closely linked to acquired immunity and can influence the development and regulation of an acquired response.
TLRs are a family of type I transmembrane receptors characterized by an NH2-terminal extracellular leucine-rich repeat domain (LRR) and a COOH-terminal intracellular tail containing a conserved region called the Toll/IL-1 receptor (TIR) homology domain. The extracellular domain contains a varying number of LRR, which are thought to be involved in ligand binding. Eleven TLRs have been described to date in humans and mice. They differ from each other in ligand specificities, expression patterns, and in the target genes they can induce.
Ligands which act via TLRs (also known as immune response modifiers (IRMS)) have been developed, for example, the imidazoquinoline derivatives described in U.S. Pat. No. 4,689,338 which include the product Imiquimod for treating genital warts, and the adenine derivatives described in WO 98/01448 and WO 99/28321.
This patent application describes a class of pyrimidine derivatives having immunomodulating properties that act via TLR7 which are useful in the treatment of viral or allergic diseases and cancers.
In accordance with the present invention, there is therefore provided a compound of formula (I)
whereinR1 represents C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthio;R2 represents either
R3 represents a hydrogen atom or a C1-C3 alkyl group;R4 represents,                (i) C3-C8 cycloalkyl, C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, C1-C6 alkoxy, C1-C6 alkylthio and C3-C6 cycloalkyl, or        (ii) a group        
                in which m is 1 or 2, q is 0, 1 or 2 and each R3 independently represents a halogen atom or a hydroxyl, methyl, cyano, trifluoromethyl, S(O)h-methyl or methoxy group;X1 represents an oxygen or sulphur atom or a group NH or CH2;X2 and X4 each independently represent a bond or an oxygen or sulphur atom;R5 and R5a each independently represent a hydrogen atom or a C1-C3 alkyl group;R6 represents a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, C1-C3 alkoxy, methylsulphonyl, methylthiazolyl and NR10R11, or R6 represents a saturated heterocyclic ring optionally substituted by C1-C6 alkyl;j is 1 or 2;each R7 independently represents a hydrogen or halogen atom or a hydroxyl, methyl, cyano, halomethoxy or methoxy group;Z1 represents a C2-C6 alkylene or C3-C8 cycloalkylene group;X3 represents NR12, >N—COR12, CONR12, NR12CO, SO2NR12, >N—SO2R12, NR12SO2, NR12CONR13 or NR13CONR12, S(O)p or O;p is 0, 1 or 2;Y1 represents a single bond or C1-C6 alkylene;A represents a monocyclic or bicyclic C6-C10 aryl or a monocyclic or bicyclic C5-C12 heteroaryl group containing 1 to 3 ring heteroatoms;R8 represents a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, NR10R11 and C1-C3 alkoxy;n is 0, 1 or 2;each R9 independently represents halogen, cyano, hydroxy, thiol, C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylthio, C1-C3 alkylsulfonyl or C1-C3 alkylsulfinyl;R10 and R11 each independently represent hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring which may optionally contain a further ring heteroatom selected from oxygen, S(O)v or NR36, the heterocyclic ring being optionally substituted by C1-C6 alkyl (which is itself optionally substituted by C1-C6 alkoxy) or di-C1-C6 alkylamino;R12 represents a hydrogen atom, a 3- to 8-membered saturated or unsaturated heterocyclic ring comprising at least one ring group O, S(O)t, N or NR14, a C1-C6 alkyl group or C3-C6 cycloalkyl group, the latter two groups being optionally substituted by one or more substituents independently selected from NR15R16 and R17, orR12 is a C1-C6 alkylene which may be linked to a carbon atom within a C2-C6 alkylene group Z1 so as to form a saturated 4- to 7-membered nitrogen-containing ring;R14, R22 and R35 each independently represent a hydrogen atom, CO2R18, S(O)wR18, COR19, or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C8 cycloalkyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen, cyano, OR20 and NR20R21;R15 and R16 each independently represent a hydrogen atom, a 3- to 8-membered saturated heterocyclic ring comprising at least one ring group O, S(O)z or NR22, C1-C6 alkyl or C3-C6 cycloalkyl, the latter two groups being optionally substituted by one or more substituents independently selected from halogen, cyano, S(O)aR23, OR24, CO2R24, OC(O)R24, SO2NR24R25, CONR24R25NR24R25, NR24SO2R26, NR24COR25, or a 3- to 8-membered saturated heterocyclic ring comprising at least one ring group O, S(O)b or NR25, orR15 and R16 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more further ring heteroatoms independently selected from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring being optionally substituted by one or more substituents independently selected from halogen, cyano, S(O)dR27, OR27, CO2R27, COR27, OC(O)R27, SO2NR27R28, CONR27R28, NR27R28, NR27SO2R29, NR27COR28, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl, aryl and heteroaryl, the latter four groups being optionally substituted by one or more substituents independently selected from halogen, cyano, S(O)fR30, OR30, CO2R30, SO2NR30R31, CONR30R31 and NR30R31;R17 represents halogen, cyano, C1-C3 haloalkoxy, CO2R32, S(O)gR32, OR32SO2NR32R34, CONR32R34, NR32SO2R33, NR32CO2R33, NR32COR34 or a 3- to 8-membered saturated heterocyclic ring comprising a ring group NR35;a, b, d, f, g, h, t, v, w and z each independently represent 0, 1 or 2;R18, R26, R29 and R33 each independently represent a C1-C6 alkyl or C3-C6 cycloalkyl group;R13, R19, R20, R21, R23, R24, R25, R27, R28, R30, R31, R32 and R34 each independently represent a hydrogen atom or a C1-C6 alkyl or C3-C6 cycloalkyl group; andR36 represents a hydrogen atom or a C1-C3 alkyl group;or a pharmaceutically acceptable salt thereof.        
In the context of the present specification, unless otherwise stated, an alkyl, alkenyl or alkynyl substituent group or an alkyl, alkenyl or alkyenyl moiety in a substituent group may be linear or branched. Examples of C1-C8 alkyl groups/moieties include methyl, ethyl, propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl and n-octyl. Examples of C2-C8 alkenyl groups/moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4-hexadienyl. Examples of C2-C8 alkynyl groups/moieties include ethynyl, 1-propynyl, 2-propynyl(propargyl) or 2-butynyl.
Similarly, an alkylene group/moiety may be linear or branched. Examples of C1-C6 alkylene groups/moieties include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene, 2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2- or 3-ethylpropylene. A C3-C8 cycloalkyl(ene) group is a cyclopropyl(ene), cyclobutyl(ene), cyclopentyl(ene), cyclohexyl(ene), cycloheptyl(ene) or cyclooctyl(ene) group. A C1-C6 haloalkyl or C1-C6 haloalkoxy substituent group/moiety will comprise at least one halogen atom, e.g. one, two, three, four or five halogen atoms, examples of which include trifluoromethyl, trifluoromethoxy or pentafluoroethyl. A C1-C6 hydroxyalkyl substituent group/moiety will comprise at least one hydroxyl group, e.g. one, two, three or four hydroxyl groups, examples of which include —CH2OH, —CH2CH2OH, —CH2CH2CH2OH and —CH(CH2OH)2. An unsaturated (heterocyclic) ring will be partially or fully unsaturated. The alkyl groups in a di-C1-C6 alkylamino group may be the same or different. When R6 represents a C1-C6 alkyl group optionally substituted by NR10R11 where R10 and R11 together with the nitrogen atom to which they are attached form an optionally substituted 4- to 7-membered saturated heterocyclic ring which may optionally contain a further ring heteroatom selected from oxygen, S(O)v or NR36, it will be appreciated that the ring may be attached to the alkyl chain via any suitable ring atom, whether a carbon atom or a heteroatom. The same comment applies to the 3- to 8-membered saturated or unsaturated heterocyclic ring defined in R12, and the heterocyclic rings defined in R15, R16 and R17.
An aryl group/moiety may contain from 6 to 10 carbon atoms and may be monocyclic or polycyclic (e.g. bicyclic or tricyclic) in which the two or more rings are fused.
Heterocyclic groups are rings which may be saturated, partially unsaturated or unsaturated, and contain from 3 to 20 atoms, at least one and suitably from 1 to 4 atoms are heteroatoms selected from oxygen, sulphur and nitrogen. Rings may be monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S, and suitably from 3 to 7 member atoms, in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocycles contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
Examples of heterocyclic groups which are saturated or partially saturated include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidine, pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and the like. Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol-2-yl, and hexahydrothiepin-4-yl. Other heterocycles include dihydro-oxathiol-4-yl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene. A suitable value for a heterocyclyl group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
Heterocyclic groups which are aromatic in nature are referred to as “heteroaryl” groups. These groups are aromatic mono-, bi-, or polycyclic heterocyclic ring incorporating one or more (for example 1-4) heteroatoms selected from N, O, and S. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl” also covers ring systems wherein at least one ring is an aromatic ring containing 1 or more heteroatoms selected from O, S and N and one or more of the other rings is a non-aromatic, saturated or partially unsaturated ring optionally containing one or more heteroatoms selected from O, S and N, for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.
For the avoidance of doubt, it should be understood that the definitions of the heterocyclic rings in formula (I) are not intended to include unstable structures or any O—O, O—S or S—S bonds and that a substituent, if present, may be attached to any suitable ring atom.
When any chemical moiety or group in formula (I) is described as being optionally substituted, it will be appreciated that the moiety or group may be either unsubstituted or substituted by one or more of the specified substituents. It will be appreciated that the number and nature of substituents will be selected so as to avoid sterically undesirable combinations.
R1 represents C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C1-C6, preferably C1-C4, alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy), or C1-C6, preferably C1-C4, alkylthio (e.g. methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio).
In an embodiment of the invention, R1 represents a C1-C6 alkyl group, particularly methyl group.
In an embodiment of the invention, R3 represents a hydrogen atom.
In an embodiment of the invention, R4 represents a C3-C8, preferably C3-C6, cycloalkyl, C1-C8, preferably C4-C8 or C5-C7, alkyl, C2-C8, preferably C4-C7, alkenyl or C2-C8, preferably C4-C7, alkynyl group, each of which may be optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxyl, C1-C6, preferably C1-C4, alkoxy, C1-C6, preferably C1-C4, alkylthio and C3-C6, preferably C5-C6, cycloalkyl.
In another embodiment, R4 represents C1-C8 alkyl group, in particular a C4-C7 alkyl group which is optionally substituted by a hydroxyl group.
In one embodiment of the invention, R2 represents a group (Ia).
In an embodiment of the invention, X1 represents a sulphur atom or, in particular, CH2.
X2 preferably represents a bond or an oxygen atom.
In one embodiment, X2 represents a bond.
R5 preferably represents a hydrogen atom.
R6 represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen, cyano, hydroxyl, C1-C3 alkoxy, methylsulphonyl, methylthiazolyl and NR10R11, or R6 represents a saturated heterocyclic ring, e.g. a 5- to 6-membered saturated heterocyclic ring such as piperidine, optionally substituted by C1-C6, preferably C1-C4, alkyl, in particular methyl.
In one aspect R6 represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, hydroxyl, C1-C3 alkoxy and NR10R11. In another aspect, R6 represents a C1-C6 alkyl group, particularly methyl group. In still another aspect, R6 represents a C1-C6 alkyl group substituted by NR10R11. Each R7 independently represents a hydrogen or halogen (e.g. fluorine, chlorine, bromine or iodine) atom or a hydroxyl, methyl, cyano, halomethoxy or methoxy group. In one aspect, j is 1 and R7 represents hydrogen, hydroxyl, fluorine or methoxy.
R10 and R11 each independently represent hydrogen, C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C3-C6, preferably C5-C6, cycloalkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 4- to 7-membered, preferably 5- to 6-membered, saturated heterocyclic ring which may optionally contain a further ring heteroatom selected from oxygen, S(O)v or NR36, the heterocyclic ring being optionally substituted by C1-C6 preferably C1-C4, alkyl (which is itself optionally substituted by C1-C6, preferably C1-C4, alkoxy, e.g. methoxy or ethoxy) or di-C1-C6 alkylamino (e.g. dimethylamino).
In one aspect R10 and R11 each independently represent hydrogen, C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C3-C6, preferably C5-C6, cycloalkyl, or R10 and R11 together with the nitrogen atom to which they are attached form a 4- to 7-membered, preferably 5- to 6-membered, saturated heterocyclic ring which may optionally contain a further ring heteroatom selected from oxygen, S(O)v or NR36.
In another aspect, R10 and R11 each represent a methyl group, or R10 and R11 together with the nitrogen atom to which they are attached form a 5- to 6-membered, saturated heterocyclic ring which may optionally contain a further ring heteroatom selected from oxygen, S(O)v or NR36, the heterocyclic ring being optionally substituted by C1-C2 alkyl (which is itself optionally substituted by methoxy) or dimethylamino.
In a further aspect, R10 and R11 each represent a methyl group, or R10 and R11 together with the nitrogen atom to which they are attached form a 6-membered saturated heterocyclic ring containing a further ring heteroatom selected from oxygen or NR36.
In an alternative embodiment, R2 represents a group (Ib).
Z1 represents a C2-C6, preferably C2-C4, alkylene or C3-C8, preferably C5-C6, cycloalkylene group. In one aspect, Z1 represents a linear C2-C6 alkylene, in particular a linear C3-C4 alkylene, group.
In one aspect, X3 represents NR12, >N—COR12, NR12CO or >N—SO2R12.
Y1 represents a single bond or a C1-C6, preferably C1-C4, alkylene group. In one aspect, Y1 represents a C1-C6 alkylene, particularly methylene, group.
X4 preferably represents a bond or an oxygen atom.
In one embodiment, X4 represents a bond.
R5a preferably represents a hydrogen atom.
A represents a monocyclic or bicyclic C6-C10 aryl or a monocyclic or bicyclic C5-C12 heteroaryl group containing 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulphur. In one aspect, A represents a phenyl ring.
R8 represents a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, hydroxyl, NR10R11 and C1-C3 alkoxy.
In one aspect, R8 represents a C1-C6 alkyl group, particularly methyl group.
When n is 1 or 2, each R9 independently represents halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, hydroxy, thiol, C1-C3 alkyl (e.g. methyl or ethyl), C1-C3 hydroxyalkyl (e.g. hydroxymethyl), C1-C3 haloalkyl (e.g. trifluoromethyl), C1-C3 alkoxy (e.g. methoxy or ethoxy), C1-C3 haloalkoxy (e.g. trifluoromethoxy), C1-C3 alkylthio (e.g. methylthio or ethylthio), C1-C3 alkylsulfonyl (e.g. methylsulfonyl) or C1-C3 alkylsulfinyl (e.g. methylsulfinyl).
In one aspect, n is 0.
R12 represents a hydrogen atom, a 3- to 8-, particularly 5- to 8-membered saturated or unsaturated heterocyclic ring comprising at least one ring group (e.g. one, two, three or four ring groups independently selected from) O, S(O)t, N or NR14, a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group or C3-C6, preferably C5-C6, cycloalkyl group, the latter two groups being optionally substituted by one or more substituents (e.g. one, two or three substituents) independently selected from NR15R16 and R17, or
R12 is a C1-C6 alkylene which may be linked to a carbon atom within a C2-C6 alkylene group Z1 so as to form a saturated 4- to 7-membered nitrogen-containing ring.
In one embodiment of the invention, R12 represents a hydrogen atom, a 5- or 6-membered saturated or unsaturated heterocyclic ring comprising one or two ring groups independently selected from N and NR14, or a C1-C6, preferably C1-C4, alkyl group optionally substituted by one or more substituents (e.g. one, two or three substituents) independently selected from NR15R16 and R17.
In a further embodiment, R12 represents a hydrogen atom, a 5-membered unsaturated heterocyclic ring comprising two ring groups independently selected from N and NR14, or a C1-C3 alkyl group optionally substituted by NR15R16 or R17.
In an embodiment of the invention, R14 represents a C1-C6 alkyl group, particularly methyl group.
R15 and R16 each independently represent a hydrogen atom, a 3- to 8-membered saturated heterocyclic ring comprising at least one ring group O, S(O)z or NR22, C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group or C3-C6, preferably C5-C6, cycloalkyl group, the latter two groups being optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, S(O)aR23, OR24, CO2R24, OC(O)R24, SO2NR24R25, CONR24R25, NR24R25, NR24SO2R26, NR24COR25, or a 3- to 8-membered saturated heterocyclic ring comprising at least one ring group O, S(O)b or NR25, or
R15 and R16 together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more (e.g. one, two or three) further ring heteroatoms independently selected from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring being optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, S(O)dR27, OR27, CO2R27, COR27, OC(O)R27, SO2NR27R28, CONR27R28, NR27R28, NR27SO2R29, NR27COR28, C1-C6, preferably C1-C4, haloalkyl, C3-C8, preferably C3-C6, cycloalkyl, C1-C6, preferably C1-C4, alkyl, aryl and heteroaryl, the latter four groups being optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen, cyano, S(O)fR30, OR30, CO2R30, SO2NR30R31, CONR30R31 and NR30R31.
In an embodiment of the invention, R15 and R16 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl group optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen, cyano, S(O)aR23, OR24, CO2R24, OC(O)R24, SO2NR24R25, CONR24R25, NR24R25, NR24SO2R26, NR24COR25, or a 3- to 8-membered saturated heterocyclic ring comprising at least one ring group O, S(O)b or NR25.
In another embodiment, R15 and R16 each independently represent a C1-C6, preferably C1-C4, more preferably C1-C2, alkyl group optionally substituted by OR24.
In an alternative embodiment, R15 and R16 together with the nitrogen atom to which they are attached form a 3- to 8-, particularly 5- to 7-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally one or more (e.g. one, two or three) further ring heteroatoms independently selected from nitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring being optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, OR27, CO2R27, COR27, C1-C6, preferably C1-C4, alkyl and aryl, the latter two groups being optionally substituted by one or more substituents (e.g. one, two, three or four substituents) independently selected from halogen, cyano, S(O)fR30, OR30, CO2R30, SO2NR30R31, CONR30R31 and NR30R31.
In a further embodiment, R15 and R16 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally a second ring nitrogen or oxygen atom, the heterocyclic ring being optionally substituted by OR27, CO2R27, COR27, C1-C3 alkyl or phenyl, the latter two groups being optionally substituted by S(O)fR30 or NR30R31.
In an embodiment of the invention, R17 represents CO2R32.
R18, R26, R29 and R33 each independently represent a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group or C3-C6, preferably C5-C6, cycloalkyl group.
R13, R19, R20, R21, R23, R24, R25, R27, R28, R30, R31, R32 and R34 each independently represent a hydrogen atom or a C1-C6, preferably C1-C4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) group or C3-C6, preferably C5-C6, cycloalkyl group.
In an embodiment of the invention,
R1 represents methyl;
R2 represents either
R3 represents a hydrogen atom;R4 represents a C4-C7 alkyl group optionally substituted by a hydroxyl group;X1 represents CH2;X2 represents a bond or an oxygen atom;R5 represents a hydrogen atom;R6 represents a C1-C6 alkyl group optionally substituted by NR10R11;j is 1;R7 represents a hydrogen or halogen (particularly fluorine) atom or a methoxy group;Z1 represents a C3-C4 alkylene;X3 represents NR12, >N—COR12, NR12CO or >N—SO2R12;Y1 represents methylene;X4 represents a bond or an oxygen atom;R5a represents a hydrogen atom;A represents a monocyclic or bicyclic C6-C10 aryl (particularly phenyl) group;R8 represents methyl;n is 0;R10 and R11 each represent a methyl group, or R10 and R11 together with the nitrogen atom to which they are attached form a 6-membered saturated heterocyclic ring containing a further ring heteroatom selected from oxygen or NR36;R12 represents a hydrogen atom, a 5-membered unsaturated heterocyclic ring comprising two ring groups independently selected from N and NR14, or a C1-C3 alkyl group optionally substituted by NR15R16 or R17;R14 represents methyl;R15 and R16 each independently represent a C1-C2 alkyl group optionally substituted by OR24, orR15 and R16 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally a second ring nitrogen or oxygen atom, the heterocyclic ring being optionally substituted by OR27, CO2R27, COR27, C1-C3 alkyl or phenyl, the latter two groups being optionally substituted by S(O)fR30 or NR30R31;f is 2;R17 represents CO2R32; andR24, R27, R30, R31 and R32 each independently represent a hydrogen atom or a methyl group.
In another embodiment of the invention,
R1 represents methyl;
R2 represents either
R3 represents a hydrogen atom;R4 represents a C4-C7 alkyl group optionally substituted by a hydroxyl group;X1 represents a sulphur atom or CH2;X2 represents a bond or an oxygen atom;R5 represents a hydrogen atom;R6 represents a C1-C6 alkyl group optionally substituted by hydroxyl, methylsulphonyl, methylthiazolyl or NR10R11, or R6 represents a 5- to 6-membered saturated heterocyclic ring optionally substituted by C1-C6 alkyl;j is 1;R7 represents a hydrogen or halogen (particularly fluorine) atom or a hydroxyl or methoxy group;Z1 represents a C3 alkylene;X3 represents NR12, >N—COR12, NR12CO or >N—SO2R12;Y1 represents methylene;X4 represents a bond or an oxygen atom;R5a represents a hydrogen atom;A represents a monocyclic or bicyclic C6-C10 aryl (particularly phenyl) group;R8 represents methyl;n is 0;R10 and R11 each represent a methyl group, or R10 and R11 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated heterocyclic ring optionally containing a further ring heteroatom selected from oxygen, S(O)v or NR36, the heterocyclic ring being optionally substituted by C1-C6 alkyl (which is itself optionally substituted by C1-C6 alkoxy) or di-C1-C6 alkylamino;v is 2;R12 represents a hydrogen atom, a 5- or 6-membered saturated or unsaturated heterocyclic ring comprising one or two ring groups independently selected from N and NR14, or a C1-C3 alkyl group optionally substituted by NR15R16 or R17;R14 represents methyl;R15 and R16 each independently represent a C1-C2 alkyl group optionally substituted by OR24, orR15 and R16 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocyclic ring comprising a ring nitrogen atom and optionally a second ring nitrogen or oxygen atom, the heterocyclic ring being optionally substituted by OR27, CO2R27, COR27, C1-C3 alkyl or phenyl, the latter two groups being optionally substituted by S(O)fR30 or NR30R31;f is 2;R17 represents CO2R32 or S(O)gR32;g is 0; andR24, R27, R30, R31 and R32 each independently represent a hydrogen atom or a methyl group.
Examples of compounds of the invention include    Methyl 2-(3-((3-(2-Amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propylamino)methyl)phenyl)acetate,    Methyl 2-(4-((3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propylamino)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate,    (S)-Methyl 1-(2-((3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)(3-(2-methoxy-2-oxoethyl)benzyl)amino)-2-oxoethyl)pyrrolidine-2-carboxylate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(4-methylpiperazin-1-yl)acetamido)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(4-hydroxypiperidin-1-yl)acetamido)methyl)phenyl)acetate,    Methyl 2-(3-((2-(4-acetyl-1,4-diazepan-1-yl)-N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)acetamido)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(4-(3-(dimethylamino)propyl)piperazin-1-yl)acetamido)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-((2-hydroxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate,    Methyl 4-((3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)(3-(2-methoxy-2-oxoethyl)benzyl)amino)-4-oxobutanoate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-4-(dimethylamino)butanamido)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)methylsulfonamido)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-1-methyl-1H-imidazole-4-sulfonamido)methyl)phenyl)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-((2-methoxyethyl)(methyl)amino)acetamido)methyl)phenyl)acetate,    Methyl 2-(3-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-3-(dimethylamino)propanamido)methyl)phenyl)acetate,    Methyl 2-(3-((4-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)butylamino)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((3-(2-amino-4-(1-hydroxyheptan-3-ylamino)-6-methylpyrimidin-5-yl)propylamino)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((N-(3-(2-amino-4-(1-hydroxyheptan-3-ylamino)-6-methylpyrimidin-5-yl)propyl)-2-(dimethylamino)acetamido)methyl)phenyl)acetate,    Methyl 2-(3-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    Methyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    Methyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    Methyl 2-(4-(2-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propylamino)-2-oxoethyl)phenyl)acetate,    Methyl 2-(3-(2-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propylamino)-2-oxoethyl)phenyl)acetate,    Methyl 2-(3-((3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propylamino)methyl)phenoxy)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(3-(4-(methylsulfonyl)phenyl)piperidin-1-yl)acetamido)methyl)phenyl)acetate,    Methyl 2-(4-((1N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-morpholinoacetamido)methyl)phenyl)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(4-phenylpiperidin-1-yl)acetamido)methyl)phenyl)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(piperidin-1-yl)acetamido)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyheptan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyhexan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyheptan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    Methyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    2-Morpholinoethyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    2-(Dimethylamino)ethyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    3-(Dimethylamino)propyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    2-(4-Methylpiperazin-1-yl)ethyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    Methyl 2-(3-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-4-hydroxyphenyl)acetate,    Methyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-3-methoxyphenoxy)acetate,    Methyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (S)-Methyl 2-(3-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-4-fluorophenyl)acetate,    5 (S)-Methyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyhexan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    Methyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyheptan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-1-methylpiperidine-4-carboxamido)methyl)phenyl)acetate,    Methyl 2-(4-((N-(3-(2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)propyl)-2-(methylthio)acetamido)methyl)phenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(2-hydroxybutylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    Methyl 2-(3-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)-4-methoxyphenyl)acetate,    3-(Dimethylamino)-2,2-dimethylpropyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    3-(4-Methylpiperazin-1-yl)propyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    4-(Dimethylamino)butyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate.    3-Morpholinopropyl 2-(4-((2-amino-4-methyl-6-(pen ylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    1-Methylpiperidin-4-yl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    4-(Pyrrolidin-1-yl)butyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    (1-(2-Methoxyethyl)piperidin-4-yl)methyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    4-(4-Methylpiperazin-1-yl)butyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    4-(1,1-Dioxidothiomorpholin-4-yl)butyl(4-{[2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl]methyl}phenyl)acetate,    4-Morpholinobutyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    2-(1-Methylpiperidin-4-yl)ethyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    Piperidin-4-ylmethyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    4-(4-(Dimethylamino)piperidin-1-yl)butyl 2-(4-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (S)-4-(Dimethylamino)butyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (S)-(1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    4-(Pyrrolidin-1-yl)butyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-(1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    (S)-(1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    Methyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    (S)-4-(Pyrrolidin-1-yl)butyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    4-(Pyrrolidin-1-yl)butyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    (S)-Methyl 2-(3-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)acetate,    (S)-(1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(2-hydroxybutylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    4-(Pyrrolidin-1-yl)butyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)acetate,    4-(Pyrrolidin-1-yl)butyl 2-(3-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(3-((2-amino-4-methyl-6-(pentylamino)pyrimidin-5-yl)methyl)phenyl)acetate,    (S)-4-(Dimethylamino)butyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    (S)-4-(4-Methylpiperazin-1-yl)butyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    (S)-Methyl 2-(4-((2-amino-4-(1-hydroxypentan-2-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    2-Hydroxyethyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    4-(4-(Dimethylamino)piperidin-1-yl)butyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    4-Hydroxybutyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    3-(Methylsulfonyl)propyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    3-Hydroxypropyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (S)-4-(Dimethylamino)butyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)phenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(4-(2-amino-4-(butylamino)-6-methylpyrimidin-5-ylthio)phenyl)acetate,    4-(Pyrrolidin-1-yl)butyl 2-(4-(2-amino-4-(butylamino)-6-methylpyrimidin-5-ylthio)phenyl)acetate,    4-(Dimethylamino)butyl 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)acetate,    Methyl 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-methoxyphenyl)acetate,    Methyl 2-(3-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-4-hydroxyphenyl)acetate,    (S)-2-(1-Methylpiperidin-4-yl)ethyl 2-(4-((2-amino-4-(1-hydroxyhexan-3-ylamino)-6-methylpyrimidin-5-yl)methyl)-3-fluorophenyl)acetate,    2-(4-Methylthiazol-5-yl)ethyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-methoxyphenyl)acetate,    (1-Methylpiperidin-4-yl)methyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,    4-(Dimethylamino)butyl 2-(4-((2-amino-4-(butylamino)-6-methylpyrimidin-5-yl)methyl)-3-hydroxyphenyl)acetate,or pharmaceutically acceptable salts thereof.
It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.
The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises
(a) when R2 represents a group of formula (Ia), reacting a compound of formula (II)
wherein j, X1, X2, R1, R3, R4, R5 and R7 are as defined in formula (I), with a compound of formula (III), R6—OH, where R6 is as defined in formula (I); or(b) when R2 represents a group of formula (Ib), reacting a compound of formula (IV)
wherein n, A, X3, X4, Y1, Z1, R1, R3, R4, R5a and R9 are as defined in formula (I), with a compound of formula (V), R8—OH, where R8 is as defined in formula (I); or(c) when R2 represents a group of formula (Ib) in which X3 represents NH and Y1 represents C1-C6 alkylene, reacting a compound of formula (VI)
wherein R1, R3, R4 and Z1 are as defined in formula (I), with a compound of formula (VII)
wherein Y2 represents —(C1-C5alkyl)j-CHO, j is 0 or 1, and A, n, X4, R5a, R8 and R9 are as defined in formula (I);and optionally after (a), (b) or (c) carrying out one or more of the following procedures:                converting a compound of formula (I) into another compound of formula (I)        removing any protecting groups        forming a pharmaceutically acceptable salt.        
Process (a) may be carried out under acidic conditions in the presence of, for example, hydrochloric or sulphuric acid and the appropriate alcohol of formula (III) as solvent. Alternatively, the reaction may be carried out by activation of the formula (II) acid with a coupling agent such as PyBop (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) or HATU (O-(7-azabezotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) in an organic solvent such as N-methylpyrrolidinone, N,N-dimethylformamide, acetonitrile or tetrahydrofuran, usually in the presence of a suitable base (e.g. triethylamine, Hunigs base) at a temperature, for example, in the range from 0 to 50° C.
Process (b) may be carried out in an analogous manner to process (a).
Process (c) may conveniently be carried out in the presence of a suitable reducing agent (e.g. sodium triacetoxyborohydride) in an organic solvent such as 1-methyl-2-pyrrolidinone, 1,2-dichloroethane or tetrahydrofuran at a temperature, for example, in the range from 0 to 150° C. Alternatively, an imine intermediate can be preformed by stirring the compounds of formulae (VI) and (VII) in a suitable solvent such as tetrahydrofuran, optionally in the presence of an acid, such as acetic acid, at a temperature, for example, in the range from room temperature to 150° C. A reducing agent, such as sodium borohydride, can then be added to give a compound of formula (I) when R2 represents a group of formula (Ib).
A compound of formula (IV) may be prepared by reacting a compound of formula (VI) with a compound of formula (VIIa) in which the substituents have the meanings defined in formula (VII), using process (c) above

Alternatively, compounds of formula (IV) may be prepared by dealkylating a corresponding compound of formula (I) according to techniques known in the art.
Compounds of formula (II) in which X1 represents CH2, X2 represents a bond and R5 represents a hydrogen atom may be prepared as described in the following reaction scheme 1 in which j, R1, R3, R4 and R7 are as defined in formula (II), Et represents an ethyl group LG represents a leaving group and R40 represents a C1-C6 alkyl group.

Compounds of formula (C) may be prepared by reacting a compound of formula (B) with a base, such as sodium hydride, in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide at a temperature, for example, from 0° C. to room temperature (20° C.), followed by addition of a compound of formula (A). The reaction is then preferably heated at a temperature, for example, from 50° C. to 100° C., optionally in the presence of an additive such as potassium iodide.
Compounds of formula (D) may be prepared by reacting a compound of formula (C) with guanidine or guanidine carbonate in a suitable solvent such as methanol or ethanol at a temperature, for example, in the range from 50° C. to 150° C.
Compounds of formula (E) may be prepared by reacting a compound of formula (D) with phosphorous oxychloride, at a temperature, for example, from 50° C. to 110° C.
Compounds of formula (F) may be prepared by reacting a compound of formula (E) with excess of an amine of formula R3R4NH, in a suitable solvent such as butanol or 1,2-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively, the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
Compounds of formula (G) may be prepared by reacting a compound of formula (F) with a reducing agent, such as lithium aluminium hydride, in a suitable solvent such as tetrahydrofuran at a temperature, for example, from 0° C. to 60° C.
Compounds of formula (H) may be prepared by reacting a compound of formula (G) with a chlorinating agent, such as thionyl chloride, in a suitable solvent such as dichloromethane at a temperature, for example, from 0° C. to 50° C.
Compounds of formula (J) may be prepared by reacting a compound of formula (H) with a cyanide salt, such as potassium cyanide, in a suitable solvent such as dimethylsulfoxide or N,N-dimethylformamide (or a mixture of both solvents) at a temperature, for example, from room temperature to 50° C.
Compounds of formula (II) may be prepared by reacting a compound of formula (J) with an alkali base, such as potassium hydroxide, in a suitable solvent such as methanol or ethanol and water at a temperature, for example, from 50° C. to 100° C.
Alternatively the order of the steps in reaction scheme 1 may be changed, for example, a compound of formula (E) can be subjected to steps (v) to (vi) then displaced by an amine R3R4NH as in step (iv).
In reaction scheme 1, compounds of formula (A) may be prepared easily using known techniques. For example, a compound of formula (A), designated (Av) in which LG represents a leaving group, R40 represents a C1-C6 alkyl group, j is 1 and R7 is hydroxyl protected by a protecting group P1.
may be prepared by the following route:

Compounds of formula (Aii) may be prepared by reacting a compound of formula (Ai) with an alkylating agent of formula, P1LG, where LG is a leaving group and P1 represents a suitable hydroxyl-protecting group such as methyl or benzyl, in the presence of a base such as potassium carbonate, in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide at a temperature, for example, from room temperature to 100° C.
Compounds of formula (Aiii) may be prepared by reacting a compound of formula (Aii) with a reducing agent, for example, diisobutylaluminium hydride (DIBAL-H) in a suitable solvent such as tetrahydrofuran at a temperature, for example, from −60° C. to room temperature.
Compounds of formula (Aiv) may be prepared by carbonylating a compound of formula (Aiii) in the presence of an alcohol, R40OH. The reaction may be performed in a carbonylator under a pressure of carbon monoxide (1-5 bar) with a palladium catalyst, such as dichloro[1,1′-bis(diphenylphosphino)ferrocene]Pd (II) dichloromethane adduct, at a temperature from 30° C. to 150° C.
Compounds of formula (Av), where LG is a chloride leaving group, may be prepared by reacting a compound of formula (Aiv), with a chlorinating agent, such as thionyl chloride, in a suitable solvent such as dichloromethane at a temperature, for example, from 0° C. to 50° C.
Compounds of formula (F) can also be prepared by reaction of a compound of formula (VIII) with excess of an amine of formula R3R4NH, where j, R1, R3, R4, R7 and R40 are as defined above and R41 is defined as a C1-C6 alkyl or a phenyl ring substituted by one or more C1-C6 alkyl groups.

The reaction may be carried out in a suitable solvent such as butanol or 1,2-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively, the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
A compound of formula (VIII) may be prepared by reacting a compound of formula (D) with a compound of formula (IX), 41RSO2Cl. The reaction may be carried out in a suitable solvent, such as DCM, and a base such as triethylamine or Hunigs base at a temperature, for example, from 0° C. to 50° C.
A compound of formula (J) may also be prepared by reaction of a compound of formula (VIIIa) with an amine of formula R3R4NH
in which the substituents have the meanings defined above. A compound of formula (VIIIa) may be prepared from a compound of formula (VIIIb) using the schemes and reaction conditions above.
A compound of formula (VIIIb) may prepared according to reaction scheme 1 steps (i) and (ii) by substituting the compound of formula (A) with a compound of formula (VIIIc) in which LG represents a leaving group, P represents a hydroxyl-protecting group and j and R7 are as defined in formula (VIIIb), followed by removal of the hydroxyl-protecting group P,

Compounds of formula (C) can also be prepared by reduction of a compound of formula (X)
wherein j, R1, R7 and R40 are as defined above. The reaction may be carried out with a catalyst such as palladium on carbon under a hydrogen atmosphere (1-20 bar) in a suitable solvent such as ethanol at a temperature, for example, from 20° C. to 100° C.
A compound of formula (X) can be prepared by reaction of a compound of formula (B) with a compound of formula (XI)
wherein j, R7 and R40 are as defined above. The reaction may be carried out in the presence of acetic acid and piperidine in a suitable solvent such as toluene at a temperature, for example, from 50° C. to 150° C.
Compounds of formula (J) may also be prepared as described in the following reaction scheme Ia:

Compounds of formula (c) may be prepared by a Heck reaction between a compound of formula (b) and a compound of formula (a) where Hal=bromine or iodine and j, R1 and R7 are as defined in reaction scheme 1. The reaction may be carried out using a palladium catalyst, such as Pd(OAc)2 or Pd-118, a base such as sodium hydrogencarbonate or dicyclohexylmethylamine, and tetrabutylammonium chloride or bromide. The reaction is performed in a suitable solvent such as tetrahydrofuran or dimethylacetamide at a temperature, for example, from 50° C. to 150° C.
Compounds of formula (d) may be prepared by reacting a compound of formula (c) with guanidine or guanidine carbonate in a suitable solvent such as methanol or ethanol at a temperature, for example, in the range from 50° C. to 150° C.
Compounds of formula (e), where LG is a leaving group such as halogen or an alkylsulphonyl or benzylsulphonyl group, may be prepared by reacting a compound of formula (d) with phosphorous oxychloride, at a temperature, for example, from 50° C. to 110° C. Alternatively a compound of formula (e) may be prepared by reacting a compound of formula (d) with, for example, an alkylsulphonyl chloride. The reaction is conveniently carried out in a solvent, such as dichloromethane, in the presence of a base such as triethylamine or Hunigs base at a temperature, for example, from 0° C. to 50° C.
Compounds of formula (J) may be prepared by reacting a compound of formula (e) with excess of an amine of formula R3R4NH, in a suitable solvent such as butanol or 1,4-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively, the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
Compounds of formula (a) are commercially available or may be prepared easily using known techniques. For example, a compound of formula (a), designated (av), in which Hal is iodine, j is 1 and R7 is hydroxyl protected by a protecting group P1 (e.g. methyl, ethyl or benzyl)
may be prepared using the route below.

Compounds of formula (aii) may be prepared by reacting a compound of formula (ai) with a reducing agent, for example, borane-tetrahydrofuran complex, in a suitable solvent such as tetrahydrofuran at a temperature, for example, from room temperature to 80° C.
Compounds of formula (aiii) may be prepared by reacting a compound of formula (aii) with an alkylating agent of formula, P1LG, where LG is a leaving group and P1 is a hydroxyl-protecting group, in the presence of a base such as potassium carbonate, in a suitable solvent such as tetrahydrofuran or N,N-dimethylformamide, at a temperature, for example, from room temperature to 100° C.
Compounds of formula (aiv), where LG is a chloride leaving group, may be prepared by reacting a compound of formula (aiii), with a chlorinating agent, such as thionyl chloride, in a suitable solvent such as dichloromethane at a temperature, for example, from 0° C. to 50° C.
Compounds of formula (av) may be prepared by reacting a compound of formula (aiv) with a cyanide salt, such as potassium cyanide, in a suitable solvent such as dimethylsulfoxide or N,N-dimethylformamide (or a mixture of both solvents) at a temperature, for example, from room temperature to 50° C.
A compound of formula (I), where R2 represents a group of formula (Ia) in which X1 represents CH2, X2 represents a bond and R5 represents a hydrogen atom, may be prepared by reacting a compound of formula (f)
in which LG represents a leaving group and j, R1, R6 and R7 are as defined in formula (I), with an amine of formula R3R4NH in which R3 and R4 are as defined in formula (I), in a suitable solvent such as 1,4-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively, the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
A compound of formula (f) may be prepared according to reaction scheme 1a above, starting with a compound of formula (c1).

A compound of formula (c1) may be prepared according to reaction scheme 1a step (i) using an appropriate aromatic bromide or iodide (g), or from a compound (h) or (j) using the methods hereinbefore described:

A compound of formula (C) in reaction scheme 1 may also be prepared using Heck chemistry as above with a compound of formula (k):

Compounds of formula (J) in reaction scheme 1a may also be prepared from a compound of formula (e) where LG is chloro, by a palladium catalysed coupling reaction with a protected amino-alcohol of formula (Pa),

The reaction may be performed in a suitable solvent such as 1,4-dioxane with a palladium catalyst formed from palladium acetate and 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene and a base such as potassium carbonate. The reaction may be performed at a temperature, for example, from 50° C. to 150° C.
A compound of formula (II) in which X1 represents a sulphur atom may be prepared by reacting a compound of formula (XII) with a compound of formula (XIII) or (XIIIa) in which j, R1, R7 and R40 are as defined above, and then by following the steps in reaction scheme 1 from formula (D), or the compound of formula (II) may be prepared from the compound of formula (XIIIb) in which j, R1 and R7 are as defined above, following reaction scheme 1 steps (vi)-(vii), (iii)-(iv) and then (viii).

The reaction may be carried out in a suitable solvent, such as ethylene glycol, and a base such as potassium carbonate at a temperature, for example, from 80° C. to 200° C.
A compound of formula (II) in which X1 represents an oxygen atom may be prepared by reacting a compound of formula (XIV) with a compound of formula (XV), where R42 represents a suitable leaving group and j, R1, R7 and R40 are as defined above, and then by following the steps in reaction scheme 1 from formula (C)

The reaction may be carried out in a suitable solvent, such as tetrahydrofuran, and a base such as potassium carbonate at a temperature, for example, from 20° C. to 100° C.
A compound of formula (II) in which X1 represents a group NH may be prepared by reacting a compound of formula (XVI) with a compound of formula (XVII) where and j, R1, R7 and R40 are as defined above, then by following the steps in reaction scheme 1 from formula (C). The benzyl protecting group may be removed by hydrogenation at a convenient step in the route.

The reaction may be carried out in a suitable solvent, such as toluene, and a catalyst such as rhodium acetate at a temperature, for example, from 50° C. to 150° C.
Compounds of formula (VI) in which Z1 represents a linear C3-C6 alkylene group may be prepared according to the following reaction scheme 2 in which PG represents a nitrogen-protecting group and R1, R3 and R4 are as defined in formula (I).

Compounds of formula (L) may be prepared by reacting a compound of formula (K) with excess of an amine of formula R3R4NH where R3 and R4 are as defined above, in a suitable solvent such as butanol or 1,2-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
Compounds of formula (M) may be prepared by reacting a compound of formula (L) with iodine in the presence of a base such as sodium hydroxide, in a suitable organic solvent such as dichloromethane and with water. The reaction is preferably performed at a temperature, for example, from 50° C. to 150° C.
Compounds of formula (N) may be prepared by reacting a compound of formula (M) with a compound of formula (XVIII), HC≡C(CH2)1-4N-PG, where PG is a nitrogen-protecting group. The reaction may be carried out in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0), copper(I) iodide and a base such as triethylamine. The reaction may be carried out in a suitable solvent, such as tetrahydrofuran, at a temperature, for example, from 50° C. to 150° C.
Compounds of formula (P) may be prepared by the reduction of a compound of formula (N) under hydrogenation conditions. The reaction may be carried out with a catalyst such as palladium on carbon under a hydrogen atmosphere (1-20 bar) in a suitable solvent such as ethanol at a temperature, for example, from 20° C. to 100° C.
Compounds of formula (VI) may be prepared by removing the nitrogen-protecting group from a compound of formula (P) according to techniques known in the art.
Alternatively the order of the steps in scheme 2 may be changed as follows:

Compounds of formula (P) may also be prepared according to reaction scheme 4, where LG1 is a leaving group and R1 and PG are as defined above.

Compounds of formula (Q) and (R) can be prepared in a similar method as shown above.
A compound of formula (S) can be prepared from a compound of formula (R) by activation of the hydroxyl group. When LG1 represents chlorine the reaction may be performed by reacting a compound of formula (R) with phosphorous oxychloride, at a temperature, for example, from 50° C. to 110° C. Alternatively when LG1 represents OSO2R41 as defined in formula (VIII), a compound of formula (R) may be reacted with a compound of formula 41RSO2Cl. The reaction may be carried out in a suitable solvent, such as dichloromethane, and a base such as triethylamine or Hunigs base at a temperature, for example, from 0° C. to 50° C.
Compounds of formula (P) may be prepared by reacting a compound of formula (S) with excess of an amine of formula R3R4NH where R3 and R4 are as defined above, in a suitable solvent such as butanol or 1,2-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
Compounds of formulae (III), (V), (VI), (VII), (VIIa), (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (X), (XI), (XII), (XIII), (XIIIa), (XIIIb), (XIV), (XV), (XVI), (XVII), (XVIII) and further compounds of formula (II) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) may be converted to other compounds of formula (I) using conventional methods. For example, a compound of formula (I) in which R2 represents a group of formula (Ib) and X3 is NH can be converted to a corresponding compound of formula (I) in which X3 is >NSO2R12 by reaction with a compound of formula R12SO2Cl. The reaction is suitably carried out in an organic solvent such as dichloromethane or acetonitrile, in the presence of a base such as pyridine or triethylamine. Temperatures in the range from 0° C. to 80° C. are suitably employed.
Further, a compound of formula (I) in which R2 represents a group of formula (Ib) and X3 is NH can be converted to a corresponding compound of formula (I) in which X3 is >NCOR12 by reaction with a compound of formula R12COCl. The reaction is suitably carried out in an organic solvent such as dichloromethane or acetonitrile, in the presence of a base such as pyridine or triethylamine. Temperatures in the range from 0° C. to 80° C. are suitably employed. Alternatively the reaction may be carried out by activation of an acid of formula R12CO2H with a coupling agent such as HATU or PyBOP in an organic solvent such as N-methylpyrrolidinone, N,N-dimethylformamide, acetonitrile or tetrahydrofuran usually in the presence of a suitable base (e.g. triethylamine, Hunigs base) at a temperature, for example, in the range from 0° C. to 50° C.
Still further, a compound of formula (I) in which R2 represents a group of formula (Ib) and X3 is NH can be converted to a corresponding compound of formula (I) in which X3 is >NCOCH2NR15R16 by reaction with chloroacetyl chloride followed by an amine of formula R15R16NH. The first stage is suitably carried out in an organic solvent such as dichloromethane or acetonitrile, with one equivalent of chloroacetyl chloride. Temperatures in the range from 0° C. to 30° C. are suitably employed. In the second stage the reaction is suitably carried out in an organic solvent such as dichloromethane or acetonitrile, with excess of an amine R15R16NH. Temperatures in the range from 0° C. to 100° C. are suitably employed.
A compound of formula (I), where R2 represents a group of formula (Ib) and X3 represents NR12CO or NR12SO2 may be prepared by reacting a compound of formula (XIX) with a compound of formula (XX)
where R50 represents SO2-LG2 or CO-LG2, LG2 is a suitable leaving group such as chlorine and the remaining substituents are as defined in formula (I). The reaction is suitably carried out in an organic solvent such as dichloromethane or acetonitrile, in the presence of a base such as pyridine or triethylamine. Temperatures in the range from 0° C. to 80° C. are suitably employed. Alternatively when R50=CO2H, the reaction may be carried out by activation with a coupling agent such as HATU, T3P (1-propanephosphonic acid cyclic anhydride) or PyBOP in an organic solvent such as N-methylpyrrolidinone, N,N-dimethylformamide, acetonitrile or tetrahydrofuran usually in the presence of a suitable base (e.g. triethylamine, Hunigs base) at a temperature, for example, in the range from 0° C. to 50° C.
A compound of formula (IV) where R2 represents a group of formula (Ib) and X3 represents NR12CO or NR12SO2, may be prepared by reaction of a compound of formula (XIX) with a compound of formula (XXI) using similar conditions to those above.

A compound of formula (XIX) may be prepared by reacting a compound of formula (VI) with an aldehyde or ketone under standard reductive amination conditions.
A compound of formula (II) where R2 represents a group of formula (XXII) may be prepared by reacting a compound of formula (XXIII) with a compound of formula (XXIV)
where R43 is H or methyl and R1, R3, R4 are as defined above. The reaction may be carried out under acid conditions, for example, in aqueous hydrochloric acid at elevated temperature.
A compound of formula (XXIII) may be prepared according to scheme 5:

A compound of formula (A2) may be prepared by reacting a compound of formula (A1) with an amine of formula R3R4NH. The reaction may be carried out in the presence of a base such as triethylamine in an organic solvent such as methanol. Temperatures in the range of 50-100° C. are preferred.
A compound of formula (A3), where R1 is methyl, may be prepared by reacting a compound of formula (A2) with tetramethylstannane. The reaction may be carried out in the presence of a catalyst such as Pd(PPh3)4 in an organic solvent such as dimethylformamide. Temperatures in the range of 50-120° C. are preferred. A compound of formula (A3), where R1 is alkoxy or alkylthiol, may be prepared by reacting a compound of formula (A2) with the appropriate alcohol, or alkylthiol in the presence of a base such as sodium hydride.
A compound of formula (A4) may be prepared by reacting a compound of formula (A3) with a reducing agent such as sodium borohydride. The reaction may be carried out in an organic solvent such as methanol at a temperature in the range of 0-50° C.
A compound of formula (I) where R2 represents a group of formula (Ia), wherein X1 is CH2 and X2 is O may be prepared by reacting a compound of formula (XXV) with a compound of formula (XXVI)
where LG3 is a leaving group such as chlorine, bromine or mesylate and j, R1, R3, R4, R5, R6 and R7 are as defined in formula (I). The reaction may be carried out in the presence of a base such as potassium carbonate in an organic solvent such as dimethylformamide at a temperature in the range from 20-100° C.
A compound of formula (XXV) may be prepared according to scheme 6 below:
where j, R1, R3, R4 and R7 are as defined above and P′ is hydrogen or a protecting group.
Compounds of formula (B2) may be prepared by reacting a compound of formula (B1) with guanidine or guanidine carbonate in a suitable solvent such as methanol or ethanol at a temperature, for example, in the range from 50° C. to 150° C.
Compounds of formula (B3) may be prepared in two steps by reacting a compound of formula (B2) with a compound of formula 41RSO2Cl, followed with an amine of formula R3R4NH. The first step may be carried out in a suitable solvent, such as DCM, and a base such as triethylamine or Hunigs base at a temperature, for example, from 0° C. to 50° C. The second step may be carried out in a suitable solvent such as butanol or 1,2-dioxane at a temperature, for example, from 50° C. to 150° C. Alternatively the reaction can be performed in a microwave at a temperature, for example, from 50° C. to 200° C.
A compound of formula (I) where R2 represents a group of formula (Ib), wherein X3 is NR12CONR13 or NR13CONR12 may be prepared by reacting a compound of formula (XXVII) with a compound of formula (XXVIII)
where R51 is defined as Cl—C(O)NR12/R13— and n, R1, R3, R4, R12, R13, Z1, Y1, A, X4, R9, R5a and R8 are as defined above. The reaction may be carried out in a suitable solvent, such as dichloromethane, and a base such as triethylamine or Hunigs base at a temperature, for example, from 0° C. to 50° C.
A compound of formula (I) where R2 represents a group of formula (Ib) may be prepared from a compound of formula (XXIX) or (XXX) using the same methods as in scheme 1 and the enabling chemistry above. This route is suitable, for example, where X3 in formulae (XXIX) and (XXX) is S(O)p or O.

Compounds of formulae (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX) and (XXX) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as phenol, hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, 1-hydroxy-2-napthoate (xinafoate), methanesulphonate or p-toluenesulphonate salt.
Compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.
The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as modulators of toll-like receptor (especially TLR7) activity, and thus may be used in the treatment of:
1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, parainfluenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, candida, aspergillus, cryptococcal meningitis, pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
Thus, the present invention provides a compound of formula (I) or a pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.
In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
In particular, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterial infections and dermatosis.
The invention still further provides a method of treating, or reducing the risk of, a disease or condition comprising or arising from abnormal cell growth (e.g. a cancer), which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
The invention also provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).
The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.
Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention (including pharmaceutically acceptable salts) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 micrometres (μm), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.
For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts thereof) may also be administered in conjunction with other compounds used for the treatment of the above conditions.
The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
The anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:
(i) other antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitors like 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase);(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases, inhibitors of the hepatocyte growth factor family, c-kit inhibitors, abl kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU111248 (sunitinib; WO 01/60814), compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
Furthermore, for the treatment of the inflammatory diseases COPD, asthma and allergic rhinitis the compounds of the invention may be combined with agents such as tumour necrosis factor alpha (TNF-alpha) inhibitors such as anti-TNF monoclonal antibodies (for example Remicade, CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (such as Enbrel); non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate, lefunomide; hydroxychloroquine, d-penicillamine, auranofin or other parenteral or oral gold preparations.
The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LTB4, LTC4, LTD4, and LTE4) selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
The present invention still further relates to the combination of a compound of the invention and a gastroprotective histamine type 2 receptor antagonist.
The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
The present invention still further relates to the combination of a compound of the invention and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
The present invention further relates to the combination of a compound of the invention and an anticholinergic agent including muscarinic receptor (M1, M2, and M3) antagonists such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
The present invention still further relates to the combination of a compound of the invention together with a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol.
The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
The present invention still further relates to the combination of a compound of the invention together with an insulin-like growth factor type I (IGF-1) mimetic.
The present invention still further relates to the combination of a compound of the invention and a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
The present invention still further relates to the combination of a compound of the invention together with an inhibitor of matrix metalloproteases (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12.
The present invention still further relates to the combination of a compound of the invention together with modulators of chemokine receptor function such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX3CR1 for the C—X3-C family.
The present invention still further relates to the combination of a compound of the invention together with a cytokine or modulator of cytokine function, including alpha-, beta-, and gamma-interferon; interleukins (IL) including IL1 to 15, and interleukin antagonists or inhibitors, including agents which act on cytokine signalling pathways.
The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (omalizumab).
The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.
In a further aspect the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined and one or more agents independently selected from:                a non-steroidal glucocorticoid receptor (GR-receptor) agonist;        a selective β2 adrenoceptor agonist (such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol);        a phosphodiesterase inhibitor (such as a PDE4 inhibitor);        a protease inhibitor (such as a neutrophil elastase or matrix metalloprotease MMP-12 inhibitor);        a glucocorticoid;        an anticholinergic agent;        a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); and        an inhibitor of kinase function (such as the kinases p38 or IKK).        
The invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is                a non-steroidal glucocorticoid receptor (GR-receptor) agonist;        a selective β2 adrenoceptor agonist;        a phosphodiesterase inhibitor;        a protease inhibitor;        a glucocorticoid;        an anticholinergic agent;        a modulator of chemokine receptor function; or        an inhibitor of kinase function;for simultaneous, sequential or separate use in therapy.        
In another aspect, the invention provides a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is                a non-steroidal glucocorticoid receptor (GR-receptor) agonist;        a selective β2 adrenoceptor agonist;        a phosphodiesterase inhibitor;        a protease inhibitor;        a glucocorticoid;        an anticholinergic agent;        a modulator of chemokine receptor function; or        an inhibitor of kinase function;and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.        
The present invention will be further explained by reference to the following illustrative examples.
Unless otherwise stated reactions were run under nitrogen and organic solutions were dried over magnesium sulphate. RPHPLC means reversed phase preparative HPLC using Waters Symmetry C8, Xterra, XBridge or Phenomenex Gemini columns using acetonitrile and either aqueous ammonium acetate, ammonia, formic acid or trifluoroacetic acid as buffer where appropriate. Column chromatography was carried out on silica gel. Treating with SCX means the mixture was absorbed on SCX and eluted with an appropriate solvent such as methanol or acetonitrile then the free base product eluted with aqueous ammonia/methanol.
The following abbreviations are used in the Examples:    EtOAc ethyl acetate    DCM dichloromethane    NMP N-methylpyrrolidinone    NBS N-bromosuccinimide    DMF N,N-dimethylformamide    DMSO dimethylsulfoxide    THF tetrahydrofuran    MeOH methanol    EtOH ethanol    TFA trifluoroacetic acid    HCl hydrogen chloride    K2CO3 potassium carbonate    NaHCO3 sodium hydrogen carbonate    TEA triethylamine    MeCN acetonitrile    Pd/C palladium on carbon    T3P 1-propanephosphonic acid cyclic anhydride    DMAP 4-dimethylaminopyridine    PS-TBD polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene    MTBE tert-butyl methyl ether    DIBAL-H diisobutylaluminium hydride    Pd-118 1,1′-Bis(di-tert-butylphosphino)ferrocenepalladium(II) chloride    KOH potassium hydroxide    sat. saturated    aq. aqueous    Et2O diethylether    DMA N,N-dimethylacetamide    TMS-Cl trimethylsilylchloride    conc. concentrated    rt room temperature    h hours    min minutes    M molar    MS mass spectrometry    PyBop Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate    HATU O-(7-azabezotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate    APCI atmospheric chemical ionisation method    ESI electron spray ionisation method    NMR nuclear magnetic resonanceInstrument Details:            XRPD—PANalytical CubiX PRO machine in Ø-Ø configuration over the scan range 2° to 40° 2Ø with 100-second exposure per 0.02° increment. The X-rays were generated by a copper long-fine focus tube operated at 45 kV and 40 mA. The wavelength of the copper X-rays was 1.5418 Å. Data was collected on zero background holders on which ˜2 mg of the compound was placed. The holder was made from a single crystal of silicon, which had been cut along a non-diffracting plane and then polished on an optically flat finish. The X-rays incident upon this surface were negated by Bragg extinction.        